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Control of tetrapyrrole biosynthesis by alternate quaternary forms of porphobilinogen synthase

Nature Structural & Molecular Biology volume 10, pages 757–763 (2003)Cite this article

Abstract

Porphobilinogen synthase (PBGS) catalyzes the first common step in the biosynthesis of tetrapyrroles (such as heme and chlorophyll). Although the predominant oligomeric form of this enzyme, as inferred from many crystal structures, is that of a homo-octamer, a rare human PBGS allele, F12L, reveals the presence of a hexameric form. Rearrangement of an N-terminal arm is responsible for this oligomeric switch, which results in profound changes in kinetic behavior. The structural transition between octamer and hexamer must proceed through an unparalleled equilibrium containing two different dimer structures. The allosteric magnesium, present in most PBGS, has a binding site in the octamer but not in the hexamer. The unprecedented structural rearrangement reported here relates to the allosteric regulation of PBGS and suggests that alternative PBGS oligomers may function in a magnesium-dependent regulation of tetrapyrrole biosynthesis in plants and some bacteria.

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Figure 1: Characteristics of wild-type human PBGS relative to the F12L variant.
Figure 2: Comparison of newly determined structure of the hexameric human PBGS variant F12L (PDB entry 1PV8) with that of the human PBGS octamer (PDB entry 1E51).
Figure 3: Characteristics of coexpressed WT+F12L.
Figure 4: The allosteric magnesium-binding site of PBGS is not present in the hexamer.
Figure 5: A proposal for the physiologically relevant interconversion of hexameric and octameric PBGS in many species whose PBGS contain the binding determinants for the allosteric magnesium.

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Acknowledgements

We thank J. Tannir (Fox Chase Cancer Center (FCCC)), S. Seeholzer (FCCC), T. Guszczynski (US National Cancer Institute (NCI)) and T. Copland (NCI) for technical support. The FCCC DNA synthesis facility, DNA sequencing facility and Research Secretarial Services were used in the preparation of this manuscript. This work was supported by the US National Institute of Environmental Health Sciences, the NCI, and by an appropriation from the Commonwealth of Pennsylvania.

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Authors and Affiliations

  1. Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, 19111-2497, Pennsylvania, USA

    Sabine Breinig, Linda Stith & Eileen K Jaffe

  2. 3-Dimensional Pharmaceuticals, Inc., 665 Stockton Drive, Exton, 19341, Pennsylvania, USA

    Jukka Kervinen

  3. Department of Biology, Haverford College, 370 Lancaster Avenue, Haverford, 19041, Pennsylvania, USA

    Andrew S Wasson & Robert Fairman

  4. Macromolecular Crystallography Laboratory, NCI-Frederick, Frederick, 21702, Maryland, USA

    Alexander Wlodawer & Alexander Zdanov

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Correspondence to Eileen K Jaffe.

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Breinig, S., Kervinen, J., Stith, L. et al. Control of tetrapyrrole biosynthesis by alternate quaternary forms of porphobilinogen synthase. Nat Struct Mol Biol 10, 757–763 (2003). https://doi.org/10.1038/nsb963

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